This invention relates to 5-heterocyclo-pyrazoles, methods of treatment and pharmaceutical compositions for the treatment of cyclooxygenase mediated diseases, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock.
Sulfonyl pyrazoles are useful in the treatment of cyclooxygenase (COX) mediated diseases, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock. Two forms of COX are now known, a constitutive isoform (COX-1) and an inducible isoform (COX-2) of which expression is upregulated at sites of inflammation (Vane, J. R.; Mitchell, et. al., Proc. Natl. Acad. Sci. USA, 1994, 91, 2046). COX-1 appears to play a physiological role and to be responsible for gastrointestinal and renal protection. On the other hand, COX-2 appears to play a pathological role and is believed to be the predominant isoform present in inflammation conditions. The therapeutic use of conventional COX inhibitors are limited due to drug associated side effects, including life threatening ulceration and renal toxicity. Compounds that selectively inhibit COX-2 would exert anti-inflammatory effects without the adverse side effects associated with COX-1 inhibition. Preferred compounds of the invention are selective COX-2 inhibitors.
A variety of sulfonylpyrazoles that inhibit COX have been described in patent publications WO 97/11704, WO 01/40216, EP 1104758, EP 1104759, and EP 1104760; U.S. Non-Provisional Patent Application No. 09/798,752, filed Mar. 2, 2001; and U.S. Non-Provisional Patent Application No. 09/824,550, filed 2 Apr. 2, 2001.
Filed simultaneously with the present application on Nov. 2, 2001, are U.S. Provisional Applications entitled xe2x80x9cHydrazinyl and Nitrogen Oxide Pyrazolesxe2x80x9d; xe2x80x9cHeterocyclo-Alkylsulfonyl Pyrazolesxe2x80x9d; xe2x80x9c5-Heteroatom-Substituted Pyrazolesxe2x80x9d; and xe2x80x9c5-(Alkylidene-Cycloalkyl)- and 5-(Alkylidene-Heterocycl)-Pyrazolesxe2x80x9d, which refer to certain pyrazole COX-2 inhibitors. The aforesaid applications are herein incorporated in their entireties by reference.
The present invention relates to compounds of the formula I: 
or the pharmaceutically acceptable salts thereof;
wherein m is 0, 1 or 3;
n is 1, 2, or 3;
wherein ring W is connected to the pyrazole ring through a nitrogen atom and is a radical selected from the group consisting of:
a) a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl ring optionally containing one to four ring heteroatoms independently selected from the groups consisting of xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, and xe2x80x94Sxe2x80x94;
b) a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl ring optionally containing one to four ring heteroatoms independently selected from the groups consisting of xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, and xe2x80x94Sxe2x80x94; wherein said saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl is fused to a a saturated, partially saturated or aromatic (3- to 7-membered)-carbocyclic ring; and
c) a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl ring optionally containing one to four ring heteroatoms independently selected from the groups consisting of xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, and xe2x80x94Sxe2x80x94; wherein said saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl is fused to a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl containing one to two ring heteroatoms independently selected from the group consisting of xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94Oxe2x80x94;
R1 is a radical selected from the group consisting of H, xe2x80x94NO2, xe2x80x94CN, (C1-C6)alkyl, (C1-C6)alkyl-SO2xe2x80x94, (C6-C10)aryl-SO2xe2x80x94, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94;
R2 is a radical selected from the group consisting of H, xe2x80x94NO2, xe2x80x94CN, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C6-C10)aryl, (C1-C9)heteroaryl, (C1-C9)heterocyclyl, (C1-C6)alkyl-Oxe2x80x94, (C3-C7)cycloalkyl-Oxe2x80x94, (C6-C10)aryl-Oxe2x80x94, (C1-C9)heteroaryl-Oxe2x80x94, (C1-C9)heterocyclyl-Oxe2x80x94, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C3-C7)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C7)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C9)heteroaryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C9)heterocyclyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C3-C7)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C7)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-NH, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, [(C3-C7)cycloalkyl]2-Nxe2x80x94, [(C6-C10)aryl]-NHxe2x80x94, [(C6-C10)aryl]2-Nxe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]-, [(C1-C9)heteroaryl]-NHxe2x80x94, [(C1-C9)heteroaryl]2-Nxe2x80x94, [(C1-C9)heterocyclyl]xe2x80x94NHxe2x80x94, [(C1-C9)heterocyclyl]2-Nxe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C3-C7)cycloalkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C3-C7)cycloalkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]-(Cxe2x95x90O)xe2x80x94, [(C1-C9)heteroaryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C9)heteroaryl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C9)heterocyclyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Sxe2x80x94 and (C1-C6)alkyl optionally substituted by one xe2x80x94OH group or by one to four fluoro substituents;
Each R3 is a radical independently selected from the group consisting of H, halo, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C6-C10)aryl, (C2-C9heterocyclyl, (C1-C6)alkyl-Oxe2x80x94, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94NH2, (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, (C6-C10)aryl-NHxe2x80x94, [(C1-C6)alkyl][((C6-C10)aryl)-N]xe2x80x94, (C1-C9)heteroaryl-NHxe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94HNxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)-[(C1-C6)alkyl-N]xe2x80x94, xe2x80x94SH, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, and (C1-C6)alkyl optionally substituted with one to four fluoro substituents;
R4 is an (C1-C6)alkyl radical, wherein said (C1-C6)alkyl radical may optionally be substituted by one to four fluoro substituents;
R5 is a radical selected from the group consisting of H, halo, xe2x80x94OH, (C1-C8)alkyl-Oxe2x80x94, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, xe2x80x94CN, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, (C6-C10)aryl-NHxe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94, (C1-C9)heteroaryl-NHxe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Sxe2x80x94, and (C1-C6)alkyl optionally substituted with one to four fluoro substituents.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, para-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
The invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine (meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
The compounds of this invention include all stereoisomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers.
The compounds of the invention also exist in different tautomeric forms. This invention relates to all tautomers of formula I.
The compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis,and trans configurations and as mixtures thereof.
Unless otherwise indicated, the term xe2x80x9cfunctional groupxe2x80x9d, refers to xe2x80x9cradicalxe2x80x9d, xe2x80x9csubstituentxe2x80x9d xe2x80x9cmoietyxe2x80x9d, or xe2x80x9csub-moietyxe2x80x9d, as defined below. The term xe2x80x9csub-functional groupxe2x80x9d refers to xe2x80x9csubstituentxe2x80x9d xe2x80x9cmoietyxe2x80x9d, orxe2x80x9csub-moietyxe2x80x9d, as defined below.
Unless otherwise indicated, the term xe2x80x9cradicalxe2x80x9d or xe2x80x9cradicalsxe2x80x9d refers to an individual member of a variable (R1, R2, R3 etc) of the compound of the formula I (e.g., R1 is a radical selected from the group consisting of H and (C1-C6)alkyl means that R1 can be either a H radical or a (C1-C6)alkyl radical).
Unless otherwise indicated, the term xe2x80x9csubstituentxe2x80x9d or xe2x80x9csubstituentsxe2x80x9d refers to a replacement of at least one atom of a radical, wherein the term xe2x80x9cradicalxe2x80x9d is as defined above, by another atom or group of atoms. For example, an (C1-C6)alkyl substituent may replace a hydrogen atom of R1 (C6-C10)aryl radical.
Unless otherwise indicated, the term xe2x80x9cmoietyxe2x80x9d or xe2x80x9cmoietiesxe2x80x9d refers to a replacement of at least one atom of a substituent, wherein the term xe2x80x9csubstituentxe2x80x9d is as defined above, by another atom or group of atoms. For example, an (C1-C6)alkyl moiety of a particular substituent (e.g., (C1-C6)alkyl, (C6-C10)aryl, or (C3-C8)cycloalkyl substituent) may replace a hydrogen atom of that substituent.
Unless otherwise indicated, the term xe2x80x9csub-moietyxe2x80x9d or xe2x80x9csub-moietiesxe2x80x9d refers to a replacement of at least one atom of a moiety, wherein the term xe2x80x9cmoietyxe2x80x9d is as defined above, by another atom or group of atoms. For example, an (C1-C6)alkyl sub-moiety of a particular moiety (e.g., (C1-C6)alkyl, (C6-C10)aryl, or (C3-C8)cycloalkyl moiety) may replace a hydrogen atom of that moiety.
Unless otherwise indicated, the term xe2x80x9c(C1-C6)alkylxe2x80x9d as well as the (C1-C6)alkyl component of other terms referred to herein (e.g., the xe2x80x9c(C1-C6)alkyl component of (C1-C6)alkyl-Oxe2x80x94), may be linear or branched (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl), wherein each of said (C1-C6)alkyl functional group, wherever they occur, may optionally be substituted by one to three sub-functional groups per (C1-C6)alkyl component independently selected from the group consisting of fluoro, xe2x80x94OH, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C1-C6)alkyl-Oxe2x80x94, oxo, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, xe2x80x94CN, xe2x80x94NO2, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, (C6-C10)aryl-NHxe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]-, (C1-C9)heteroaryl-NHxe2x80x94, (C1-C10)heterocyclyl-NHxe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl-Oxe2x80x94, (C1-C9)heteroaryl-Oxe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-S(=O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94(C1-C6)alkyl-NH and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94.
Unless otherwise indicated, the term xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo or iodo.
Unless otherwise indicated, the term ""saturated, partially saturated or aromatic (3- to 7-membered)heterocyclyl containing 1 to 4 ring heteroatoms independently selected from xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94xe2x80x9d, as used herein, means a monocyclic (3- to 7-membered)heterocyclyl ring covalently bound to the pyrazole nucleus via a ring nitrogen atom. Said ring may contain optional double bonds so as to include saturated, partially saturated or aromatic (3- to 7-membered)heterocyclyl rings. Examples of the monocyclic aromatic ring systems are pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, triazol-1-yl, tetrazol-1-yl, isoxazol-2-yl, oxazol-3-yl, thiazol-3-yl, isothiazol-2-yl, oxadiazol-2-yl, oxadiazol-3-yl, oxatriazol-2-yl, oxatriazol-3-yl, oxatriazol-4-yl, pyridin-1-yl, pyridazin-1-yl, pyrimidin-1-yl, pyrazin-1-yl, triazin-1-yl, and the like. Examples of said monocyclic saturated or partially saturated ring systems are aziridin-1-yl, piperidin-1-yl, piperazin-1-yl, [1,3]-oxazolidin-3-yl, isothiazolidin-2-yl, [1,3]-thiazolidin-3-yl, [1,2]-pyrazolidin-1-yl, [1,3]-pyrazolidin-1-yl, thiomorpholin-4-yl, 1,2-tetrahydrothiazin-3-yl, 1,3-tetrahydrotriazin-3-yl, tetrahydrothiadiazolyl, morpholin-4-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-3-yl, azepan-1-yl, azocan-1-yl, [1,4]-diazepan-1-yl and the like.
Unless otherwise indicated, the term xe2x80x9csaturated, partially saturated or aromatic (3- to 7-membered)heterocyclyl fused to a saturated, partially saturated or aromatic (3- to 7-membered)-carbocyclic ringxe2x80x9d, as used herein, means a bicyclic ring having a first (3- to 7-membered)-heterocyclyl ring covalently bound to the pyrazole nucleus via a ring nitrogen atom and wherein said first ring is fused to a second ring comprising a 3 to 7 membered heterocyclyl ring, wherein said second 3 to 7 members include the atoms common to both rings. Said first and second rings comprise saturated, partially saturated or aromatic (3- to 7-membered)heterocyclyl rings. Examples of said bicyclic ring systems are indolidin-1-yl, indolizin-4-yl, quinolidin-1-yl, isoquinolidin-2-yl, quinazolidin-1-yl, quinazolidin-3-yl, indol-1-yl, isoindol-2-yl, cyclopentapyrid-1-yl, cyclopentapyrid-3-yl, benzoxazol-2-yl, cinnolin-1-yl, cinnolin-2-yl and the like.
Unless otherwise indicated, the term xe2x80x9csaturated, partially saturated or aromatic (3- to 7-membered)heterocyclyl fused to a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclylxe2x80x9d as used herein, means a bicyclic heterocyclyl ring having a first ring covalently bound to the pyrazole nucleus via a ring nitrogen atom and containing five to six ring atoms comprising one to two heteroatoms each independently selected from xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, xe2x80x94[Nxe2x80x94(C1-C4)alkyl]-, xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94; wherein said first ring is fused to a second ring comprising a 3 to 7 membered heterocyclyl ring, wherein said second 3 to 7 members include the atoms common to both rings. Said second ring comprises a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl ring. Examples of said bicyclic ring systems are pyrano[3,4b]pyrrol-1-yl, pyrano[3,2b]pyrrol-1-yl, pyrano[4,3b]pyrrol-1-yl, purin-1-yl, purin-3-yl, purin-7-yl, purin-9-yl, pteridin-1-yl, pteridin-3-yl, pteridin-5-yl, pteridin-8-yl, pyrido[3,4b]pyridin-1-yl, pyrido[3,2b]pyridin-1-yl, pyrido[4,3b]pyridin-1-yl, naphthyrid-1-yl, naphthyridi-8-yl and the like.
Unless otherwise indicated, the term xe2x80x9c(C2-C6)alkenylxe2x80x9d means straight or branched hydrocarbon chain functional groups of 2 to 6 carbon atoms having at least one double bond including, but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, or 2-butenyl.
Unless otherwise indicated, the term xe2x80x9c(C2-C6)alkynylxe2x80x9d is used herein to mean straight or branched hydrocarbon chain functional groups of 2 to 6 carbon atoms having one triple bond including, but not limited to, ethynyl (xe2x80x94Cxe2x89xa1Cxe2x80x94H), propynyl (xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94H or xe2x80x94Cxe2x89xa1Cxe2x80x94CH3), or butynyl (xe2x80x94CH2xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94H, or xe2x80x94CH2xe2x80x94Cxe2x89xa1xe2x80x94Cxe2x80x94CH3, or xe2x80x94Cxe2x89xa1xe2x80x94Cxe2x80x94CH2CH3).
Unless otherwise indicated, the term xe2x80x9c(C3-C7)cycloalkylxe2x80x9d refers to a mono or bicyclic carbocyclic ring functional groups including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, bicyclo[2.2.1 ]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl; wherein said (C3-C7)cycloalkyl functional groups may optionally contain 10r 3 double bonds including, but not limited to, cyclopentenyl, cyclohexenyl and cycloheptenyl.
Unless otherwise indicated, the term xe2x80x9c(C6-C10)arylxe2x80x9d means aromatic functional groups such as phenyl, naphthyl, tetrahydronaphthyl, or indanyl, wherein said (C6-C10)aryl is optionally substituted on any ring carbon atom by one to two sub-functional groups per ring, wherein said substituents are independently selected from the group consisting of halo, xe2x80x94OH, xe2x80x94CN, xe2x80x94SH, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94NO2, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C6-C10)aryl, (C1-C9)heteroaryl, (C1-C9)heterocyclyl, (C1-C6)alkyl-Oxe2x80x94, xe2x80x94OCF3, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, (C6-C10)aryl-NHxe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94, (C1-C9)heteroaryl-NHxe2x80x94, (C1-C10)heterocyclyl-NHxe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94 (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94HNxe2x80x94(C1-C6)alkyl-NH, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94.
Unless otherwise indicated, the term xe2x80x9c[(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94xe2x80x9d has the following structure: 
wherein the term xe2x80x9c(C1-C6)alkylxe2x80x9d and the term xe2x80x9c(C6-C10)arylxe2x80x9d are as defined above.
Unless otherwise indicated, the term xe2x80x9c[(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94xe2x80x9d has the following structure: 
wherein the term xe2x80x9c(C1-C6)alkylxe2x80x9d and the term xe2x80x9c(C6-C10)arylxe2x80x9d are as defined above.
Unless otherwise indicated, the term xe2x80x9c(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94HNxe2x80x94(C1-C6)alkyl-NHxe2x80x9d has the following structure: 
wherein the term xe2x80x9c(C1-C6)alkylxe2x80x9d is as defined above.
Unless otherwise indicated, the term xe2x80x9coxoxe2x80x9d refers to xe2x95x90O.
Unless otherwise indicated, the term xe2x80x9c(C1-C9)heteroarylxe2x80x9d refers to aromatic or multicyclic ring functional groups wherein at least one ring of the aromatic or multicyclic ring is aromatic, wherein said aromatic or multicyclic ring contain one or more heteroatoms selected from the group consisting of O, S and N. The (C1-C9)heteroaryl ring can also be optionally substituted by one or more oxo sub-functional groups. Examples of heteroaryl functional groups include, but are not limited to, benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (C1-C10)heteroaryl is optionally substituted on any atom(s) capable of forming an additional bond by one or two sub-functional groups independently selected from halo, xe2x80x94CN, xe2x80x94OH, (C1-C6)alkyl, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkyl-Oxe2x80x94, (C1-C6)alkyl-Oxe2x80x94 and (C3-C8)cycloalkyl-Oxe2x80x94. Unless otherwise indicated, the foregoing (C1-C9)heteroaryls can be C-attached or N-attached where such is possible. For instance, pyrrolyl can be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
Unless otherwise indicated, the term xe2x80x9c(C1-C9)heterocyclylxe2x80x9d refers to a cyclic ring functional groups containing 1 to 9 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of N, O and S. The heterocyclyl ring functional groups can be optionally substituted where such is possible by oxo, xe2x80x94CN, xe2x80x94OH, (C1-C6)alkyl, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkyl-Oxe2x80x94, (C1-C6)alkyl-Oxe2x80x94 and (C3-C8)cycloalkyl-Oxe2x80x94. Examples of the cyclic ring functional groups include, but not limited to, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]-heptanyl, azetidinyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, hexahydroazepinyl, hexahydropyrimidine, imidazolidinyl, imidazolinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, quinolizinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl or trithianyl. Unless otherwise indicated, the foregoing heterocyclyl functional groups can be C-attached or N-attached where such is possible. For example, piperidinyl can be piperidin-1-yl (N-attached) or piperidin4-yl (C-attached).
In an embodiment of the present invention, ring W is
a) a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl ring optionally containing one to four ring heteroatoms independently selected from the groups consisting of xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, and xe2x80x94Sxe2x80x94; and n is 10r 3.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted aromatic (5- to 6-membered)-heterocyclyl ring selected from the group consisting of optionally substituted pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, triazol-1-yl, tetrazol-1-yl, isoxazol-2-yl, oxazol-3-yl, thiazol-3-yl, isothiazol-2-yl, oxadiazol-2-yl, oxadiazol-3-yl, oxatriazol-2-yl, oxatriazol-3-yl, oxatriazol-4-yl, pyridin-1-yl, pyridazin-1-yl, pyrimidin-1-yl, pyrazin-1-yl, and triazin-1-yl; preferably selected from the group consisting of optionally substituted pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, triazol-1-yl, tetrazol-1-yl, pyridin-1-yl, pyridazin-1-yl, pyrimidin-1-yl, pyrazin-1-yl, and triazin-1-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted aromatic (5- to 6-membered)-heterocyclyl ring selected from the group consisting of optionally substituted isoxazol-2-yl, oxazol-3-yl, thiazol-3-yl, isothiazol-2-yl, oxadiazol-2-yl, oxadiazol-3-yl, oxatriazol-2-yl, oxatriazol-3-yl, and oxatriazol-4-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted saturated, partially saturated (3- to 7-membered)-heterocyclyl ring selected from the group consisting of aziridin-1-yl, piperidin-1-yl, piperazin-1-yl, [1,3]-oxazolidin-3-yl, isothiazolidin-2-yl, [1,3]-thiazolidin-3-yl, [1,2]-pyrazolidin-1-yl, 1,3-pyrazolidin-1-yl, thiomorpholin-4-yl, 1,2-tetrahydrothiazin-3-yl, 1,3-tetrahydrotriazin-3-yl, tetrahydrothiadiazolyl, morpholin-4-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-3-yl, azepan-1-yl, azocan-1-yl, [1,4]-diazepan-1-yl; preferably selected from the group consisting of piperidin-1-yl, piperazin-1-yl, [1,2]-pyrazolidin-1-yl, [1,3]-pyrazolidin-1-yl, 1,3-morpholin-4-yl, azepan-1-yl, azocan-1-yl, and [1,4]-diazepan-1-yl; more preferably selected from the group consisting of morpholin-4-yl, azepan-1-yl, azocan-1-yl, and [1,4]-diazepan-1-yl; most preferably selected from the group consisting of azepan-1-yl, azocan-1-yl, and [1,4]-diazepan-1-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted saturated, partially saturated (3- to 7-membered)-heterocyclyl ring selected from the group consisting of optionally substituted [1,3]-oxazolidin-3-yl, isothiazolidin-2-yl, [1,3]-thiazolidin-3-yl, [1,2]-pyrazolidin-1-yl, [1,3]-pyrazolidin-1-yl, thiomorpholin-4-yl, 1,2-tetrahydrothiazin-3-yl, 1,3-tetrahydrotriazin-3-yl, tetrahydrothiadiazolyl, morpholin-4-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-3-yl.
In another embodiment of the present invention, ring W is optionally substituted aziridin-1-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted piperidin-1-yl and piperazin-1-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted [1,3]-oxazolidin-3-yl, isothiazolidin-2-yl, and [1,3]-thiazolidin-3-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted [1,2]-pyrazolidin-1-yl and [1,3]-pyrazolidin-1-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted thiomorpholin-4-yl, 1,2-tetrahydrothiazin-3-yl, 1,3-tetrahydrotriazin-3-yl, tetrahydrothiadiazolyl, and morpholin-4-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, and 1,4-oxazin-3-yl.
In a preferred embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted azepan-1-yl, azocan-1-yl, and [1,4]-diazepan-1-yl.
In another embodiment of the present invention, ring W is
b) a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl ring optionally containing one to four ring heteroatoms independently selected from the groups consisting of xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, and xe2x80x94Sxe2x80x94; wherein said saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl is fused to a saturated, partially saturated or aromatic (3- to 7-membered)-carbocyclic ring; and n is 1 or 3.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted indolidin-1-yl, indolizin4-yl, quinolidin-1-yl, isoquinolidin-2-yl, quinazolidin-1-yl, quinazolidin-3-yl, indol-1-yl, isoindol-2-yl, cyclopentapyrid-1-yl, cyclopentapyrid-3-yl, benzoxazol-2-yl, cinnolin-1-yl, and cinnolin-2-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted indolidin-1-yl and indolizin-4-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted quinolidin-1-yl and isoquinolidin-2-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted quinazolidin-1-yl and quinazolidin-3-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted indol-1-yl and isoindol-2-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted cyclopentapyrid-1-yl and cyclopentapyrid-3-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted benzoxazol-2-yl, cinnolin-1-yl, and cinnolin-2-yl.
In another embodiment of the present invention, ring W is
c) a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl ring optionally containing one to four ring heteroatoms independently selected from the groups consisting of xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, and xe2x80x94Sxe2x80x94; wherein said saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl is fused to a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl containing one to two ring heteroatoms independently selected from the group consisting of xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94Oxe2x80x94; and n is 1 or 3.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted pyrano[3,4b]pyrrol-1-yl, pyrano[3,2b]pyrrol-1-yl, pyrano[4,3b]pyrrol-1-yl, purin-1-yl, purin-3-yl, purin-7-yl, purin-9-yl, pteridin-1-yl, pteridin-3-yl, pteridin-5-yl, pteridin-8-yl, pyrido[3,4b]pyridin-1-yl, pyrido[3,2b]pyridin-1-yl, pyrido[4,3b]pyridin-1-yl, naphthyrid-1-yl, and naphthyridi-8-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted pyrano[3,4b]pyrrol-1-yl, pyrano[3,2b]pyrrol-1-yl, and pyrano[4,3b]pyrrol-1-yl
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted purin-1-yl, purin-3-yl, purin-7-yl, and purin-9-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted pteridin-1-yl, pteridin-3-yl, pteridin-5-yl, and pteridin-8-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted pyrido[3,4b]pyridin-1-yl, pyrido[3,2b]pyridin-1-yl and pyrido[4,3b]pyridin-1-yl.
In another embodiment of the present invention, ring W is a radical selected from the group consisting of optionally substituted naphthyrid-1-yl and naphthyridi-8-yl.
In another embodiment of the present invention, each R3 is a radical independently selected from the group consisting of H, halo, (C3-C7)cycloalkyl, (C6-C10)aryl, (C2-C9)heterocyclyl, (C1-C6)alkyl-Oxe2x80x94, and (C1-C6)alkyl optionally substituted with one to four fluoro substituents.
In another embodiment of the present invention, each R3 is a radical independently selected from the group consisting of H and (C1-C6)alkyl optionally substituted with one to four fluoro substituents; and n is 1 or 3; preferably H and methyl.
In another embodiment of the present invention, each R3is a radical independently selected from the group consisting of methyl, ethyl and pyrrolidinyl.
In another embodiment of the present invention, each R3is halo; preferably chloro or bromo.
In another embodiment of the present invention, each R3 is a radical independently selected from the group consisting of (C3-C7)cycloalkyl, (C6-C10)aryl, and (C2-C9)heterocyclyl.
In another embodiment of the present invention, each R3 is a radical independently selected from the group consisting of (C1-C6)alkyl-Oxe2x80x94 and (C1-C6)alkyl optionally substituted with one to four fluoro substituents; preferably one to three fluoro substituents.
In another embodiment of the present invention, n is 1.
In another embodiment of the present invention, n is 1 or 3.
In another embodiment of the present invention, n is 1 or 2.
In a preferred embodiment of the present invention, ring W is piperidinyl; R3 is pyrrolidinyl; and n is 1.
In another embodiment of any of the foregoing embodiments of the invention, R1 is H, xe2x80x94NO2, or xe2x80x94CN, preferably R1 is xe2x80x94CN.
In another embodiment of any of the foregoing embodiments of the invention, R1 is Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94.
In another embodiment of any of the foregoing embodiments of the invention, R1 is H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94.
In another preferred embodiment of any of the foregoing embodiments of the invention, R2 is a radical selected from the group consisting of H, xe2x80x94NO2, xe2x80x94CN, and (C1-C6)alkyl optionally substituted by one xe2x80x94OH or by one to four fluoro substituents; preferably R2 is an (C1-C6)alkyl radical optionally substituted by one xe2x80x94OH or by one to four fluoro substituents; more preferably R2 is xe2x80x94CF3 or xe2x80x94CHF2.
In another embodiment of any of the foregoing embodiments of the invention, R2 is a radical selected from the group consisting of (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C6-C10)aryl, (C1-C9)heteroaryl, and (C1-C9)heterocyclyl.
In another embodiment of any of the foregoing embodiments of the invention, R2 is a radical selected from the group consisting of (C1-C6)alkyl-Oxe2x80x94, (C3-C7)cycloalkyl-Oxe2x80x94, (C6-C10)aryl-Oxe2x80x94, (C1-C9)heteroaryl-Oxe2x80x94, and (C1-C9)heterocyclyl-Oxe2x80x94.
In another embodiment of any of the foregoing embodiments of the invention, R2 is a radical selected from the group consisting of Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C3-C7)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94, and (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94.
In another embodiment of any of the foregoing embodiments of the invention, R2 is a radical selected from the group consisting of (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C7)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C9)heteroaryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94 and (C1-C9)heterocyclyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94.
In another embodiment of any of the foregoing embodiments of the invention, R2 is a radical selected from the group consisting of (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C3-C7)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, and (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94.
In another embodiment of any of the foregoing embodiments of the invention, R2 is a radical selected from the group consisting of (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C7)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, and (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94.
In another embodiment of any of the foregoing embodiments of the invention, R2 is a radical selected from the group consisting of (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, [(C3-C7)cycloalkyl]2-Nxe2x80x94, [(C6-C10)aryl]-NHxe2x80x94, [(C6-C10)aryl]2-Nxe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94, [(C1-C9)heteroaryl]-NHxe2x80x94, [(C1-C9)heteroaryl]2-Nxe2x80x94, [(C1-C9)heterocyclyl]-NHxe2x80x94, and [(C1-C9)heterocyclyl]2-Nxe2x80x94.
In another embodiment of any of the foregoing embodiments of the invention, R2 is a radical selected from the group consisting of H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94.
In another embodiment of any of the foregoing embodiments of the invention, R2 is a radical selected from the group consisting of [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C3-C7)cycloalkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C3-C7)cycloalkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C9)heteroaryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C9)heteroaryl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C9)heterocyclyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Sxe2x80x94.
In another embodiment of any of the foregoing embodiments of the invention, R4 is a radical selected from the group consisting of sec-butyl isobutyl, tert-butyl, and ethyl.
In a preferred embodiment of the present invention, R4 is methyl or trifluoromethyl.
In another embodiment of any of the foregoing embodiments of the invention, R5 is is a radical selected from the group consisting of H, halo and xe2x80x94CN.
In another embodiment of any of the foregoing embodiments of the invention, R5 is xe2x80x94OH or (C1-C6)alkyl-Oxe2x80x94 radical.
In another embodiment of any of the foregoing embodiments of the invention, R5 is (C2-C6)alkenyl or (C2-C6)alkynyl radical.
In another embodiment of any of the foregoing embodiments of the invention, R5is a (C3-C7)cycloalkyl radical.
In another embodiment of any of the foregoing embodiments of the invention, R5 is Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, or (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94.
In another embodiment of any of the foregoing embodiments of the invention, R5 is a radical selected from the group consisting of (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, (C6-C10)aryl-NHxe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94, and (C1-C9)heteroaryl-NHxe2x80x94.
In another embodiment of any of the foregoing embodiments of the invention, R5 is a radical selected from the group consisting of H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94.
In another embodiment of any of the foregoing embodiments of the invention, R5 is (C1-C6)alkyl-Sxe2x80x94.
In a preferred embodiment of the present invention, R5 is H.
Examples of specific preferred compounds of the formula I are the following:
3-Difluoromethyl-1-(4-methanesulfonyl-phenyl)-5-(3-methyl-piperidin-1-yl)-1H-pyrazole-4-carbonitrile;
4-1-(4-methanesulfonyl-phenyl)-5-(3-methyl-piperidin-1-yl)-1H-pyrazole-4-carbonitrile;
4-1-(4-methanesulfonyl-phenyl)-5-(4-methyl-piperidin-1-yl)-1H-pyrazole-4-carbonitrile;
5-Azepan-1-yl-1-(4-methanesulfonyl-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;
5-[1,4]Diazepan-1-yl-1-(4-methanesulfonyl-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;
1-(4-Methanesulfonyl-phenyl)-5-(4-methyl-[1,4]diazepan-1-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;
1-(4-MethanesuIfonyl-phenyl)-3-trifluoromethyl-5-(3,3,5-trimethyl-azepan-1-yl)-1H-pyrazole-4-carbonitrile;
5-(4-Acetyl-[1,4]diazepan-1-yl)-1-(4-methanesulfonyl-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;
5-(4-Acetyl-[1,4]diazepan-1-yl)-3-difluoromethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile;
5-Azepan-1-yl-3-difluoromethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile;
5-[1,4]Diazepan-1-yl-3-difluoromethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile;
3-Difluoromethyl-1-(4-methanesulfonyl-phenyl)-5-(4-methyl-[1,4]diazepan-1-yl)-1H-pyrazole-4-carbonitrile;
3-Difluoromethyl-1-(4-methanesulfonyl-phenyl)-5-(3,3,5-trimethyl-azepan-1-yl)-1H-pyrazole-4-carbonitrile;
5-Azepan-1-yl-1-(5-methanesulfonyl-pyridin-2-yl )-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde; and
5-Azepan-1-yl-1-(4-methanesulfonyl-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid methyl ester; or
the pharmaceutically acceptable salts thereof.
The present invention also relates to a pharmaceutical composition for the treatment of a condition selected from the group consisting of arthritis (including osteoarthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), fever (including rheumatic fever and fever associated with influenza and other viral infections), common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn""s disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer""s disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostrate cancer; hematopoietic malignancies including leukemias and lymphomas; Hodgkin""s disease; aplastic anemia, skin cancer and familiar adenomatous polyposis), tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington""s disease, Parkinson""s disease, migraine, depression, peripheral neuropathy, pain (including low back and neck pain, headache and toothache), gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, comeal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders (such as psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes (including types I and II diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats), sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet""s syndrome, hypersensitivity, kidney disease, Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoan diseases (such as malaria, giardia, coccidia), reproductive disorders (preferably in livestock) and septic shock (preferably arthritis, fever, common cold, pain and cancer) in a mammal, preferably a human, cat, livestock or a dog, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in such treatment and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for the treatment of a condition that can be treated by selectively inhibiting COX-2 in a mammal, preferably a human, cat, livestock or dog, comprising a COX-2 selective inhibiting effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for the treatment of a condition selected from the group consisting of inflammatory diseases such as arthritis (including osteoarthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), or fever (including rheumatic fever and fever associated with influenza).
The present invention also relates to a method for treating a condition selected from the group consisting of arthritis (including osteoarthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), fever (including rheumatic fever and fever associated with influenza and other viral infections), common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn""s disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer""s disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostrate cancer; hematopoietic malignancies including leukemias and lymphomas; Hodgkin""s disease; aplastic anemia, skin cancer and familiar adenomatous polyposis), tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington""s disease, Parkinson""s disease, migraine, depression, peripheral neuropathy, pain (including low back and neck pain, headache and toothache), gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders (such as psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes (including types I and 11 diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats), sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet""s syndrome, hypersensitivity, kidney disease, Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoan diseases (such as malaria, giardia, coccidia), reproductive disorders (preferably in livestock) and septic shock (preferably arthritis, fever, common cold, pain and cancer) in a mammal, preferably a human, cat, livestock or a dog, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in treating such a condition.
The present invention also relates to a method for treating a disorder or condition that can be treated by selectively inhibiting COX-2 in a mammal, preferably a human, cat, livestock or a dog, comprising administering to a mammal requiring such treatment a COX-2 selective inhibiting effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for treating a condition selected from the group consisting of inflammatory diseases such as arthritis (including osteoarthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), or fever (including rheumatic fever and fever associated with influenza).
The term xe2x80x9ctreatingxe2x80x9d, as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
The term xe2x80x9clivestock animalsxe2x80x9d as used herein refers to domesticated quadrupeds, which includes those being raised for meat and various byproducts, e.g., a bovine animal including cattle and other members of the genus Bos, a porcine animal including domestic swine and other members of the genus Sus, an ovine animal including sheep and other members of the genus Ovis, domestic goats and other members of the genus Capra; domesticated quadrupeds being raised for specialized tasks such as use as a beast of burden, e.g., an equine animal including domestic horses and other members of the family Equidae, genus Equus, or for searching and sentinel duty, e.g., a canine animal including domestic dogs and other members of the genus Canis; and domesticated quadrupeds being raised primarily for recreational purposes, e.g., members of Equus and Canis, as well as a feline animal including domestic cats and other members of the family Felidae, genus Felis.
The term xe2x80x9cselectivexe2x80x9d as used herein, refers to COX-1/COX-2 IC50 inhibition ratio of 5 or greater as determined for one of the in vitro, in vivo, or ex vivo assays described on pages 41-45.
The term xe2x80x9cCompanion animalsxe2x80x9d as used herein refers to cats, dogs and horses. As used herein, the term xe2x80x9cdog(s)xe2x80x9d denotes any member of the species Canis familiaris, of which there are a large number of different breeds. While laboratory determinations of biological activity may have been carried out using a particular breed, it is contemplated that the inhibitory compounds of the present invention will be found to be useful for treating pain and inflammation in any of these numerous breeds. Dogs represent a particularly preferred class of patients in that they are well known as being very susceptible to chronic inflammatory processes such as osteoarthritis and degenerative joint disease, which in dogs often results from a variety of developmental diseases, e.g., hip dysplasia and osteochondrosis, as well as from traumatic injuries to joints. Conventional NSAIDs, if used in canine therapy, have the potential for serious adverse gastrointestinal reactions and other adverse reactions including kidney and liver toxicity. Gastrointestinal effects such as single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestine, are usually debilitating, but can often be severe or even fatal.
The term xe2x80x9ctreating reproductive disorders (preferably in livestock)xe2x80x9d as used herein refers to the use of the COX-2 inhibitors of the invention in mammals, preferably livestock animals (cattle, pigs, sheep, goats or horses), during the estrus cycle to control the time of onset of estrus by blocking the uterine signal for lysis of the corpus luteum, i.e. F-series prostaglandins, then removing the inhibition when the onset of estrus is desired. There are settings where it is useful to control or synchronize the time of estrus, especially when artificial insemination or embryo transfer are to be performed. Such use also includes enhancing the rate of embryo survival in pregnant livestock animals. Blocking F-series prostaglandin release can have several beneficial actions including reducing uterine contractions, enhancing uteroplacental bloodflow, supporting recognition of pregnancy and postponing lysis of the corpus luteum at the time when estrus would have occurred had the animal not become pregnant (around Day 21 of pregnancy). Such treatment also abrogates the effects of stress on reproduction. For example reductions in fertility caused by excessive heat, negative energy balance and other stresses which have a COX-2 mediated component, as does abortion induced by stress such as heat, transportation, co-mingling, palpation, infection, etc. Such treatment is also useful to control the time of parturition, which is accompanied by release of F-series prostaglandins that lead to lysis of the corpus luteum. Inhibition of COX-2 would block the onset of premature labor in livestock animals, allowing the offspring time to mature before birth. Also there are settings where controlling the time of parturition is a useful tool for management of pregnant animals.
The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 13O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the formula I. This invention also encompasses methods of treating disorders that can be treated by the selective inhibition of COX-2 comprising administering prodrugs of compounds of the formula I. Compounds of formula I having free amino, amido, hydroxy, carboxylic acid ester, sulfonamide or carboxylic groups (especially alkyl-Sxe2x80x94 and alkyl-(Sxe2x95x90O)xe2x80x94) can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain. Prodrugs also include metabolically labile groups such as ethers, acetates, mercaptans and sulfoxides.
One of ordinary skill in the art will appreciate that the compounds of the invention are useful in treating a diverse array of diseases. One of ordinary skill in the art will also appreciate that when using the compounds of the invention in the treatment of a specific disease that the compounds of the invention may be combined with various existing therapeutic agents used for that disease.
For the treatment of rheumatoid arthritis, the compounds of the invention may be combined with agents such as TNF-xcex1 inhibitors such as anti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules (such as Enbrel(copyright)), low dose methotrexate, lefunimide, hydroxychloroquine, d-penicilamine, auranofin or parenteral or oral gold.
The compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents to be used in combination include standard non-steroidal anti-inflammatory agents (hereinafter NSAID""s) such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib and rofecoxib, analgesics and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalgan and synvisc.
This invention also relates to a method of or a pharmaceutical composition for treating inflammatory processes and diseases comprising administering a compound of formula I of this invention or its salt to a mammal including a human, cat, livestock or dog, wherein said inflammatory processes and diseases are defined as above and said inhibitory compound is used in combination with one or more other therapeutically active agents under the following conditions:
A.) where a joint has become seriously inflammed as well as infected at the same time by bacteria, fungi, protozoa and/or virus, said inhibitory compound is administered in combination with one or more antibiotic, antifungal, antiprotozoal and/or antiviral therapeutic agents;
B.) where a multi-fold treatment of pain and inflammation is desired, said inhibitory compound is administered in combination with inhibitors of other mediators of inflammation, comprising one or more members independently selected from the group consisting essentially of:
(1) NSAIDs;
(2) H1-receptor antagonists;
(3) kinin-B1- and B2-receptor antagonists;
(4) prostaglandin inhibitors selected from the group consisting of PGD-, PGF- PGI2- and PGE-receptor antagonists;
(5) thromboxane A2 (TXA2-) inhibitors;
(6) 5-, 12- and 15-lipoxygenase inhibitors;
(7) leukotriene LTC4-, LTD4/LTE4- and LTB4-inhibitors;
(8) PAF-receptor antagonists;
(9) gold in the form of an aurothio group together with one or more hydrophilic groups;
(10) immunosuppressive agents selected from the group consisting of cyclosporine, azathioprine and methotrexate;
(11) anti-inflammatory glucocorticoids;
(12) penicillamine;
(13) hydroxychloroquine;
(14) anti-gout agents including colchicine; xanthine oxidase inhibitors including allopurinol; and uricosuric agents selected from probenecid, sulfinpyrazone and benzbromarone;
C. where older mammals are being treated for.disease conditions, syndromes and symptoms found in geriatric mammals, said inhibitory compound is administered in combination with one or more members independently selected from the group consisting essentially of:
(1) cognitive therapeutics to counteract memory loss and impairment;
(2) anti-hypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, hypertension, myocardial ischemia, angina, congestive heart failure and myocardial infarction, selected from the group consisting of:
a. diuretics;
b. vasodilators;
c. xcex2-adrenergic receptor antagonists;
d. angiotensin-II converting enzyme inhibitors (ACE-inhibitors), alone or optionally together with neutral endopeptidase inhibitors;
e. angiotensin II receptor antagonists;
f. renin inhibitors;
g. calcium channel blockers;
h. sympatholytic agents;
i. xcex12-adrenergic agonists;
j. xcex1-adrenergic receptor antagonists; and
k. HMG-CoA-reductase inhibitors (anti-hypercholesterolemics);
(3) antineoplastic agents selected from:
a. antimitotic drugs selected from:
i. vinca alkaloids selected from:
xe2x80x83[1] vinblastine and
xe2x80x83[2] vincristine;
(4) growth hormone secretagogues;
(5) strong analgesics;
(6) local and systemic anesthetics; and
(7) H2-receptor antagonists, proton pump inhibitors and other gastroprotective agents.
The active ingredient of the present invention may be administered in combination with inhibitors of other mediators of inflammation, comprising one or more members selected from the group consisting essentially of the classes of such inhibitors and examples thereof which include, matrix metalloproteinase inhibitors, aggrecanase inhibitors, TACE inhibitors, leucotriene receptor antagonists, IL-1 processing and release inhibitors, ILra, H1-receptor antagonists; kinin-B1- and B2-receptor antagonists; prostaglandin inhibitors such as PGD-, PGF- PGI2- and PGE-receptor antagonists; thromboxane A2 (TXA2-) inhibitors; 5- and 12-lipoxygenase inhibitors; leukotriene LTC4-, LTD4/LTE4- and LTB4-inhibitors; PAF-receptor antagonists; gold in the form of an aurothio group together with various hydrophilic groups; immunosuppressive agents, e.g., cyclosporine, azathioprine and methotrexate; anti-inflammatory glucocorticoids; penicillamine; hydroxychloroquine; anti-gout agents, e.g., colchicine, xanthine oxidase inhibitors, e.g., allopurinol and uricosuric agents, e.g., probenecid, sulfinpyrazone and benzbromarone.
The compounds of the present invention may also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine and antimetabolites such as methotrexate.
The compounds of the present invention may also be used in combination with anti-hypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, including hypertension, myocardial ischemia including angina, congestive heart failure and myocardial infarction, selected from vasodilators such as hydralazine, xcex2-adrenergic receptor antagonists such as propranolol, calcium channel blockers such as nifedipine, xcex12-adrenergic agonists such as clonidine, xcex1-adrenergic receptor antagonists such as prazosin and HMG-CoA-reductase inhibitors (anti-hypercholesterolemics) such as lovastatin or atorvastatin.
The active ingredient of the present invention may also be administered in combination with one or more antibiotic, antifungal, antiprotozoal, antiviral or similar therapeutic agents.
The compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as L-dopa, requip, mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists and inhibitors of neuronal nitric oxide synthase) and anti-Alzheimer""s drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate.
The compounds of the present invention may also be used in combination with osteoporosis agents such as roloxifene, lasofoxifene, droloxifene or fosomax and immunosuppressant agents such as FK-506 and rapamycin.
The present invention also relates to the formulation of the active agents of the present invention alone or with one or more other therapeutic agents which are to form the intended combination, including wherein said different drugs have varying half-lives, by creating controlled-release forms of said drugs with different release times which achieves relatively uniform dosing; or, in the case of non-human patients, a medicated feed dosage form in which said drugs used in the combination are present together in admixture in said feed composition. There is further provided in accordance with the present invention co-administration in which the combination of drugs is achieved by the simultaneous administration of said drugs to be given in combination; including co-administration by means of different dosage forms and routes of administration; the use of combinations in accordance with different but regular and continuous dosing schedules whereby desired plasma levels of said drugs involved are maintained in the patient being treated, even though the individual drugs making up said combination are not being administered to said patient simultaneously.
The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, ring W, m, n, R1, R2, R3, R4, and R5 in the reaction schemes and discussion that follow are as defined above. 
Scheme 1 refers to the preparation of a compound of formula I.
Referring to Scheme 1, a compound of the formula I can be prepared by reacting a compound of formula 11, wherein R6 is a leaving group, with a compound of the formula 
wherein ring W, R3 and n are as defined above in the presence of a fluoride containing salt and in the presence of a solvent.
The above compounds of the formula 
are commercially available or can be prepared according to the methods described in Jerry March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition, 1992, and references cited therein.
Suitable leaving groups R6 of the compound of formula 11 include halo, such as fluoro, chloro, iodo, or bromo. Other suitable leaving groups R6 include (C1-C6)alkyl-SO3xe2x80x94, such as CH3xe2x80x94SO3xe2x80x94, CF3xe2x80x94SO3xe2x80x94, or CF3CF2xe2x80x94SO3xe2x80x94. Other suitable leaving groups R6 include (C6-C10)aryl-SO3xe2x80x94, such as tosyl-SO3xe2x80x94 or phenyl-SO3xe2x80x94. Other suitable leaving groups R6 include (C1-C6)alkyl-SO2xe2x80x94, such as CH3xe2x80x94SO2xe2x80x94; or (C6-C10)aryl-SO2xe2x80x94, such as phenyl-SO2xe2x80x94. Preferably, the leaving group R6 is halo, such as chloro; or (C1-C6)alkyl-SO3xe2x80x94, such as CF3xe2x80x94SO3xe2x80x94, or CF3CF2xe2x80x94SO3xe2x80x94.
Suitable fluoride containing salts include a metal salt, such as lithium, sodium, potassium, cesium, magnesium, calcium, strontium and barium. Other suitable fluoride salts include tetra(C1-C8)alkylammonium fluoride, such as tetrabutylammonium fluoride; or (C1-C16)alkyltri(C1-C2)alkylammonium fluoride, such as cetyltrimethylammonium fluoride.
The aforesaid reaction can be performed in the presence of about 0.05 to about 10 equivalents; more preferably about 0.05 to about 5 equivalents; most preferably about 0.1 to about 2 equivalents; of the fluoride containing salts relative to the compound of formula I.
Unless otherwise indicated, the term xe2x80x9cequivalentsxe2x80x9d refers to the number of moles of the fluoride containing salt relative to the number of moles of the compound of the formula I.
Suitable solvents used in the aforesaid reaction include acetonitrile, dichloromethane, chloroform, tetrahydrofuran, dichloroethane, dimethylsulfoxide, dimethylformamide, dimethylacetamide, or acetone.
The aforesaid reaction can be performed at a temperature of about 10xc2x0 C. to about 100xc2x0 C., preferably about 20xc2x0 C. to about 80xc2x0 C. The aforesaid reaction can be performed for a period from about 2 hours to about 96 hours, preferably from about 12 hours to about 48 hours.
In the aforesaid reaction, when the fluoride containing salt is a metal salt such as potassium fluoride or cesium fluoride; preferred solvents include dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetone, or acetonitrile. Preferably, the aforesaid reaction is performed at a temperature of about 1 0C to about 30xc2x0 C. Preferably, the aforesaid reaction is performed in the presence of about 0.05 to about 5 equivalents of the fluoride containing salts relative to the compound of formula I.
In the aforesaid reaction, when the fluoride containing salt is tetra(C1-C8)alkylammonium fluoride or (C1-C16)alkyltri(C1-C2)alkylammonium fluoride; preferred solvents include acetonitrile, dichloromethane, chloroform, tetrahydrofuran, or dichloroethane. Preferably, the aforesaid reaction is performed at a temperature of about 20xc2x0 C. to about 80xc2x0 C. Preferably, the aforesaid reaction is performed in the presence of about 0.1 to about 2 equivalents of the fluoride containing salts relative to the compound of formula I.
Scheme 2 illustrates methods of preparing compounds of the formula II, which are intermediates useful in preparing compounds of the formula I in Scheme 1.
Referring to Scheme 2, a compound of the formula II wherein R6 is halo can be prepared by reacting a compound of the formula III with a halogenating agent in a polar solvent. Suitable halogenating agents include oxalyl chloride, POCl3, POBr3, SOCl2 or PCl5, preferably POCl3. Suitable solvents include methylene chloride, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP), preferably methylene chloride. The aforesaid reaction is generally carried out at a temperature from about 20xc2x0 C. to about 140xc2x0 C., preferably at about the reflux temperature of the polar solvent, preferably when the solvent is methylene chloride, the temperature is 55xc2x0 C. The aforesaid reaction is generally carried out for a period from about 1 hour to about 48 hours, preferably about 2 hours to about 24 hours.
A compound of the formula II wherein R6 contains a xe2x80x94SO3xe2x80x94, such as (C1-C6)alkyl-SO3xe2x80x94 or (C6-C10)aryl-SO3xe2x80x94, can be prepared by reacting a compound of the formula III with a sulfonylating agent in a polar solvent. Suitable sulfonylating agents include trifluoromethanesulfonic anhydride, methanesulfonyl chloride, or methanesulfonyl anhydride, preferably methanesulfonyl chloride. Suitable solvents for the aforesaid reaction include methylene chloride, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP), preferably methylene chloride. The aforesaid reaction is generally carried out at a temperature from about xe2x88x9210xc2x0 C. to about 25xc2x0 C., preferably at about 0xc2x0 C. The aforesaid reaction is generally carried out for a period from about 1 hour to about 48 hours.
A compound of the formula II wherein said R6 contains a xe2x80x94SO2xe2x80x94, such as (C1-C6)alkyl-SO2xe2x80x94 or (C6-C10)aryl-SO2xe2x80x94, can be prepared by reacting a compound of the formula II wherein R6 is halo or contains a xe2x80x94SO3xe2x80x94, as defined above, with a sulfonating agent in a polar solvent. Suitable sulfonating agents include NaSO3CH3 or NaSO3(C6-C10)aryl. Other suitable sulfonating agents include NaS(C1-C6)alkyl, such as NaSCH3, or NaS(C6-C10)aryl, such as NaS(C6H5), followed by an oxidizing agent, such as OXONE(copyright), metachloroperbenzoic acid, or hydrogen peroxide. Suitable solvents for the aforesaid reaction include DMF, DMA, or DMSO, preferably DMSO. The aforesaid reaction is generally carried out at a temperature from about minus 10xc2x0 C. to about 120xc2x0 C., preferably at about 100xc2x0 C. The aforesaid reaction is generally carried out for a period from about 1 hour to about 48 hours, preferably about 4 hours to about 24 hours.
Compounds of the formula III can be prepared by reacting a compound of formula IV, wherein the ring of the formula (R5)-A-(SOmR4) is as defined above, with a reagent of the formula 
wherein R is (C1-C6)alkyl, such as methyl; in a suitable solvent under acidic, neutral or basic conditions. Preferably, the reagent is 4,4,4-trifluoro-3-oxo-butyric acid methyl ester. Suitable solvents include methanol, ethanol, DMF, DMSO, water or a mixture thereof. Suitable acids include hydrochloric acid or trifluoroacetic acid. Suitable bases include sodium hydroxide, potassium hydroxide and potassium carbonate. The aforesaid reaction is generally carried out at a temperature from about 0xc2x0 C. to about 140xc2x0 C., preferably at about 20xc2x0 C. to about 100xc2x0 C., most preferably at about 20xc2x0 C. to about 100xc2x0 C. The aforesaid reaction is generally carried out for a period from about 1 hour to about 24 hours, preferably from about 6 hours to about 16 hours.
The above reagents of formula R2-(Cxe2x95x90O)xe2x80x94CH(R1)-(Cxe2x95x90O)xe2x80x94OR are commercially available or can be prepared according to the methods described in Jerry March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition, 1992, and references cited therein.
Compounds of formula IV are commercially available or can be made by methods well known to those of ordinary skill in the art or according to Scheme 3. For example, compounds of formula IV can be prepared by the method described in Vavrina, et al,. Collection Czechoslov. Chem. Commun., Vol. 37, 1721 (1972), which is incorporated herein by reference.
Scheme 3 refers to a preparation of a compound of the formula IV, which are intermediates useful in preparing compounds of the formula II in Scheme 2. Referring to Scheme 3, a compound of the formula IV can be prepared by reacting a compound of the formula V, wherein L2 is a leaving group, and m is 1 or 3, with hydrazine (preferably anhydrous hydrazine) in the presence of a polar solvent. Suitable leaving groups L2 include halo, triflate, or methylsulfonyl, preferably halo, such as chloro and bromo. Suitable solvents include alcohol (such as ethanol, methanol, propanol or butanol), DMSO, DMF, DMA, or NMP, preferably alcohol, most preferably ethanol. This reaction can be carried out at a temperature from about 0xc2x0 C. to about 140xc2x0 C., preferably at about the reflux temperature of the solvent. This reaction can be carried out for a period of from about 1 hour to about 36 hours, preferably from about 2 hours to about 24 hours. Preferably the product is isolated as a salt, such as a hydrobromide or hydrochloride salt. The hydrochloride salt is preferred.
The compound of the formula IV wherein m is 0 can be prepared by reacting a compound of the formula VI wherein L2 is a leaving group, with hydrazine (preferably anhydrous hydrazine) in the presence of a polar solvent, under the condition described in the aforesaid paragraph.
The compound of the formula V can be prepared by reacting a compound of the formula VI, wherein L2 is a leaving group, with an oxidizing reagent in the presence of a solvent. Suitable oxidizing agents include meta-chloroperbenzoic acid, hydrogen peroxide, sodium perborate, or OXONE(copyright), preferably OXONE(copyright). Suitable solvents or solvent mixtures include methanol-water, dioxane-water, tetrahydrofuran-water, methylene chloride, or chloroform, preferably methanol-water or methylene chloride. The aforesaid reaction can be carried out at a temperature from about 0xc2x0 C. to about 60xc2x0 C., preferably the temperature may range from about 20xc2x0 C. to about 25xc2x0 C. (i.e. room temperature). The aforesaid reaction can be carried out for a period of from about 0.5 hours to about 24 hours, preferably about 16 hours. The compounds of the formula VI can be prepared from a compound of formula VII, wherein each of L1 and L2 independently is a leaving group, by reacting said compound of the formula VII with a sulfur reagent in the presence or absence of a base in a polar solvent. Suitable leaving groups L1 include halo or methyl-SO2xe2x80x94, preferably halo, such as bromo or iodo.
Suitable leaving groups L2 halo or methyl-SO2xe2x80x94, preferably halo, such as bromo or iodo. Suitable sulfur reagents include (C1-C6)alkyl-SH, (C1-C6)alkyl-Sxe2x80x94Sxe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-SO3xe2x80x94, NaSxe2x80x94(C1-C6)alkyl or KSxe2x80x94(C1-C6)alkyl. Suitable bases include sodium hydroxide, triethylamine, alkyllithiums (such as n-butyllithium, sec-butyllithium and tert-butyllithium) and lithium diisopropylamide. Suitable solvents include dialkylethers (such as dimethylether), alcohol (such as methanol, ethanol and tert-butanol), THF, benzene, toluene, xylene, DMF, DMSO, dioxane, 1,2-dimethoxyethane and a mixture of an alcohol and water. The aforesaid reaction can be carried out at a temperature from about xe2x88x9278xc2x0 C. to 200xc2x0 C., preferably the temperature may range from about xe2x88x9278xc2x0 C. to about 120xc2x0 C. The aforesaid reaction can be carried out for a period of from about 1 minute to about 24 hours.
Compounds of the formula VII (i.e., a compound of the formulae VIIA1-VIIA7, respectively, as defined above) may be prepared by methods well known to those of ordinary skill in the art (see for example, EP 1104760).
Unless indicated otherwise, the pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere).
Those skilled in the art will appreciate that the above schemes describe general methods for preparing the compounds of the invention. Specific compounds of formula I may possess sensitive functional groups that require protecting groups when prepared with the intermediates described. Examples of suitable protecting groups may be found in T. W. Greene and P. Wuts, Protecting Groups in Organic Synthesis, John Wiley and Sons, 2nd Edition, New York, 1991.
The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
Those compounds of the formula I which are also acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I. These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields.
The compounds of formula I of the invention can, be used in a pharmaceutical composition for the treatment of a condition selected from the group consisting of arthritis (including osteoarthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), fever (including rheumatic fever and fever associated with influenza and other viral infections), common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn""s disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis,: chronic obstructive pulmonary disease, Alzheimer""s disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostrate cancer; hematopoietic malignancies including leukemias and lymphomas; Hodgkin""s disease; aplastic anemia, skin cancer and familiar adenomatous polyposis), tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington""s disease, Parkinson""s disease, migraine, depression, peripheral neuropathy, pain (including low back and neck pain, headache and toothache), gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders (such as psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes (including types I and II diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats), sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet""s syndrome, hypersensitivity, kidney disease, Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoan diseases (such as malaria, giardia, coccidia), reproductive disorders (preferably in livestock) and septic shock (preferably arthritis, fever, common cold, pain and cancer) in a mammal, preferably a human, cat, livestock or a dog, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in such treatment and a pharmaceutically acceptable carrier.
The compounds of formula I of the invention can also be used in a pharmaceutical composition for the treatment of a disorder or condition that can be treated by selectively inhibiting COX-2 in a mammal, preferably a human, cat, livestock or dog, comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The compounds of formula I of the invention can also be used in a pharmaceutical composition for the treatment of a condition selected from the group consisting of inflammatory diseases such as arthritis (including osteoarthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), or fever (including rheumatic fever and fever associated with influenza).
The compounds of formula I of the invention can also be used in a method for treating a condition selected from the group consisting of arthritis (including osteoarthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), fever (including rheumatic fever and fever associated with influenza and other viral infections), common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn""s disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer""s disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostrate cancer; hematopoietic malignancies including leukemias and lymphomas; Hodgkin""s disease; aplastic anemia, skin cancer and familiar adenomatous polyposis), tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington""s disease, Parkinson""s disease, migraine, depression, peripheral neuropathy, pain (including low back and neck pain, headache and toothache), gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders (such as psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursitis, bums, diabetes (including types I and 11 diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats), sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet""s syndrome, hypersensitivity, kidney disease, Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoan diseases (such as malaria, giardia, coccidia), reproductive disorders (preferably in livestock) and septic shock (preferably arthritis, fever, common cold, pain and cancer) in a mammal, preferably a human, cat, livestock or a dog, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in treating such a condition.
The compounds of formula I of the invention can also be used in a method for treating a disorder or condition that can be treated by selectively inhibiting COX-2 in a mammal, preferably a human, cat, livestock or a dog, comprising administering to a mammal requiring such treatment a COX-2 selective inhibiting effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The activity of the compounds of the formula I of the present invention may be demonstrated by the following assays.
Human Cell-based COX-1 Assay
Human peripheral blood obtained from healthy volunteers can be diluted to 1/10 volume with 3.8% sodium citrate solution. The platelet-rich plasma immediately obtained can be washed with 0.14 M sodium chloride containing 12 mM Tris-HCl (pH 7.4) and 1.2 mM EDTA. Platelets can be washed with platelet buffer (Hanks buffer (Ca free) containing 0.2% BSA and 20 mM Hepes). Finally, the human washed platelets (HWP) can be suspended in platelet buffer at the concentration of 2.85xc3x97108 cells/ml and stored at room temperature until use. The HWP suspension (70 xcexcl aliquots, final 2.0xc3x97107 cells/ml) can be placed in a 96-well U bottom plate and 10 xcexcl aliquots of 12.6 mM calcium chloride added. Platelets can be incubated with A23187 (final 10 xcexcM, Sigma) with test compound (0.1-100 xcexcM) dissolved in DMSO (final concentration; less than 0.01%) at 37xc2x0 C. for 15 minutes. The reaction can be stopped by addition of EDTA (final 7.7 mM) and Txc3x97B2 in the supernatant quantitated by using a radioimmunoassay kit (Amersham) according to the manufacturer""s procedure.
Human cell-based COX-2 Assay
The human cell based COX-2 assay can be carried out as previously described (Moore et al., Inflam. Res., 45, 54, 1996). Confluent human umbilical vein endothelial cells (HUVECs, Morinaga) in a 96-well flat bottom plate can be washed with 80 ml of RPMI1640 containing 2% FBS and incubated with hIL-1xcex2 (final concentration 300 U/ml, R and D Systems) at 37xc2x0 C. for 24 hours. After washing, the activated HUVECs can be incubateed with test compound (final concentration; 0.1nM-1 xcexcM) dissolved in DMSO (final concentration; less than 0.01%) at 37xc2x0 C. for 20 minutes and stimulated with A23187 (final concentration 30 mM) in Hanks buffer containing 0.2% BSA, 20 mM Hepes at 37xc2x0 C. for 15 minutes. 6-Keto-PGF1xcex1, stable metabolite of PGI2, in the supernatant can be quantitated by using a radioimmunoassay method (antibody; Preseptive Diagnostics, SPA; Amersham).
Canine In vitro Assays
The following canine cell based COX 1 and COX-2 assays have been reported in Ricketts et al., Evaluation of Selective Inhibition of Canine Cyclooxyaenase 1 and 2 by Carprofen and Other Nonsteroidal Anti-inflammatory Drugs, American Journal of Veterinary Research, 59 (11), 1441-1446.
Protocol for Evaluation of Canine COX-1 Activity
Test drug compounds can be solubilized and diluted the day before the assay can be to be conducted with 0.1 mL of DMSO/9.9 mL of Hank""s balanced salts solution (HBSS) and stored overnight at 4xc2x0 C. On the day that the assay can be carried out, citrated blood can be drawn from a donor dog, centrifuged at 190xc3x97g for 25 minutes at room temperature and the resulting platelet-rich plasma can be transferred to a new tube for further procedures. The platelets can be washed by centrifuging at 1500xc3x97g for 10 minutes at room temperature. The platelets can be washed with platelet buffer comprising Hank""s buffer (Ca free) with 0.2% bovine serum albumin (BSA) and 20 mM HEPES. The platelet samples can be adjusted to 1.5xc3x97107/mL, after which 50 xcexcl of calcium ionophore (A23187) together with a calcium chloride solution can be added to 50 xcexcl of test drug compound dilution in plates to produce final concentrations of 1.7 xcexcM A23187 and 1.26 mM Ca. Then, 100 xcexcl of canine washed platelets can be added and the samples can be incubated at 37xc2x0 C. for 15 minutes, after which the reaction can be stopped by adding 20 xcexcl of 77 mM EDTA. The plates can be centrifuged at 2000xc3x97g for 10 minutes at 4xc2x0 C., after which 50 xcexcl of supernatant can be assayed for thromboxane B2 (TXB2) by enzyme-immunoassay (EIA). The pg/mL of TXB2 can be calculated from the standard line included on each plate, from which it can be possible to calculate the percent inhibition of COX-1 and the IC50 values for the test drug compounds.
Protocol for Evaluation of Canine COX-2 Activity
A canine histocytoma (macrophage-like) cell line from the American Type Culture Collection designated as DH82, can be used in setting up the protocol for evaluating the COX-2 inhibition activity of various test drug compounds. There can be added to flasks of these cells 10 xcexcg/mL of LPS, after which the flask cultures can be incubated overnight. The same test drug compound dilutions as described above for the COX-1 protocol can be used for the COX-2 assay and can be prepared the day before the: assay can be carried out. The cells can be harvested from the culture flasks by scraping and can be washed with minimal Eagle""s media (MEM) combined with 1% fetal bovine serum, centrifuged at 1500 rpm for 2 minutes and adjusted to a concentration of 3.2xc3x97105 cells/mL. To 50 xcexcl of test drug dilution there can be added 50 xcexcl of arachidonic acid in MEM to give a 10 xcexcM final concentration and there can be added as well 100 xcexcl of cell suspension to give a final concentration of 1.6xc3x97105 cells/mL. The test sample suspensions can be incubated for 1 hour and then centrifuged at 1000 rpm for 10 minutes at 4xc2x0 C., after which 50 xcexcl aliquots of each test drug sample can be delivered to EIA plates. The EIA can be performed for prostaglandin E2 (PGE2) and the pg/mL concentration of PGE2 can be calculated from the standard line included on each plate. From this data it can be possible to calculate the percent inhibition of COX-2 and the IC50 values for the test drug compounds. Repeated investigations of COX-1 and COX-2 inhibition can be conducted over the course of several months. The results are averaged and a single COX-1: COX-2 ratio is calculated.
Whole blood assays for COX-1 and COX-2 are known in the art such as the methods described in C. Brideau, et al., A Human Whole Blood Assay for Clinical Evaluation of Biochemical Efficacy of Cyclooxycqenase Inhibitors, Inflammation Research, Vol. 45, pp. 68-74 (1996). These methods may be applied with feline, canine or human blood as needed.
Carrageenan Induced Foot Edema in Rats
Male Sprague-Dawley rats (5 weeks old, Charles River Japan) can be fasted overnight. A line can be drawn using a marker above the ankle on the right hind paw and the paw volume (V0) can be measured by water displacement using a plethysmometer (Muromachi). Animals can be given orally either vehicle (0.1% methyl cellulose or 5% Tween 80) or a test compound (2.5 ml per 100 g body weight). One hour later, the animals can be injected intradermally with -carrageenan (0.1 ml of 1% w/v suspension in saline, Zushikagaku) into right hind paw (Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544, 1962; Lombardino et al., Arzneim. Forsch., 25, 1629, 1975) and three hours later, the paw volume (V3) can be measured and the increase in volume (V3xe2x88x92V0) calculated. Since maximum inhibition attainable with classical NSAIDs is 60-70%, ED30 values can be calculated.
Gastric Ulceration in Rats
The gastric ulcerogenicity of test compound can be assessed by a modification of the conventional method (Ezer et al., J. Pharm. Pharmacol., 28, 655, 1976; Cashin et al., J. Pharm. Pharmacol., 29, 330-336, 1977). Male Sprague-Dawley rats (5 weeks old, Charles River Japan), fasted overnight, can be given orally either vehicle (0.1% methyl cellulose or 5% Tween 80) or a test compound (1 ml per 100 g body weight). Six hours after, the animals can be sacrificed by cervical dislocation. The stomachs can be removed and inflated with 1% formalin solution (10 ml). Stomachs can be opened by cutting along the greater curvature. From the number of rats that showed at least one gastric ulcer or haemorrhaging erosion (including ecchymosis), the incidence of ulceration can be calculated. Animals did not have access to either food or water during the experiment.
Canine Whole Blood ex vivo Determinations of COX-1 and COX-2 Activity Inhibition
The in vivo inhibitory potency of a test compound against COX-1 and COX-2 activity may be evaluated using an ex vivo procedure on canine whole blood. Three dogs can be dosed with 5 mg/kg of the test compound administered by oral gavage in 0.5% methylcellulose vehicle and three dogs can be untreated. A zero-hour blood sample can be collected from all dogs in the study prior to dosing, followed by 2- and 8-hour post-dose blood sample collections. Test tubes can be prepared containing 2 xcexcL of either (A) calcium ionophore A23187 giving a 50 xcexcM final concentration, which stimulates the production of thromboxane B2 (TXB2) for COX-1 activity determination; or of (B) lipopolysaccharide (LPS) to give a 10 xcexcg/mL final concentration, which stimulates the production of prostaglandin E2 (PGE2) for COX-2 activity determination. Test tubes with unstimulated vehicle can be used as controls. A 500 xcexcL sample of blood can be added to each of the above-described test tubes, after which they can be incubated at 37xc2x0 C. for one hour in the case of the calcium ionophore-containing test tubes and overnight in the case of the LPS-containing test tubes. After incubation, 10 xcexcL of EDTA can be added to give a final concentration of 0.3%, in order to prevent coagulation of the plasma which sometimes occurs after thawing frozen plasma samples. The incubated samples can be centrifuged at 4xc2x0 C. and the resulting plasma sample of xcx9c200 xcexcL can be collected and stored at xe2x88x9220xc2x0 C. in polypropylene 96-well plates. In order to determine endpoints for this study, enzyme immunoassay (EIA) kits available from Cayman can be used to measure production of TXB2 and PGE2, utilizing the principle of competitive binding of tracer to antibody and endpoint determination by colorimetry. Plasma samples can be diluted to approximate the range of standard amounts which would be supplied in a diagnostic or research tools kit, i.e., 1/500 for TXB2 and 1/750 for PGE2.
The data set out in Table 1 below show how the percent inhibition of COX-1 and COX-2 activity is calculated based on their zero hour values. The data is expressed as treatment group averages in pg/ml of TXB2 and PGE2 produced per sample. Plasma dilution can be not factored in said data values.
The data in Table 1 show that, in this illustration, at the 5 mg/kg dose there can be significant COX-2 inhibition at both timepoints. The data in Table 1 also show that at the 5 mg/kg dose there can be no significant inhibition of COX-1 activity at the timepoints involved. Accordingly, the data in Table 1 clearly demonstrates that at the 5 mg/kg dosage concentration this compound possesses good COX-2 selectivity.
COX inhibition is observed when the measured percent inhibition is greater than that measured for untreated controls. The percent inhibition in the above table is calculated in a straightforward manner in accordance with the following equation:       %    ⁢          xe2x80x83        ⁢    inhibition    ⁢          xe2x80x83        ⁢          (              2        ⁢                  -                ⁢        hour            )        =                    (                                            PGE              2                        ⁢                          xe2x80x83                        ⁢            at            ⁢                          xe2x80x83                        ⁢            t                    =          0                )            -              (                                            PGE              2                        ⁢                          xe2x80x83                        ⁢            at            ⁢                          xe2x80x83                        ⁢            t                    =          2                )                    (                                    PGE            2                    ⁢                      xe2x80x83                    ⁢          at          ⁢                      xe2x80x83                    ⁢          t                =        0            )      
Data Analysis
Statistical program packages, SYSTAT (SYSTAT, INC.) and StatView (Abacus Cencepts, Inc.) for Macintosh can be used. Differences between test compound treated group and control group can be tested for using ANOVA. The IC50 (ED30) values can be calculated from the equation for the log-linear regression line of concentration (dose) versus percent inhibition.
Most compounds prepared in the Working Examples as described hereinafter can be tested by at least one of the methods described above and showed IC50 values of 0.001 xcexcM to 3 xcexcM with respect to inhibition of COX-2 in either the canine or human assays.
COX-2 selectivity can be determined by ratio in terms of IC50 value of COX-1 inhibition to COX-2 inhibition. In general, it can be said that a compound showing a COX-1/COX-2 inhibition ratio of more than 5 has good COX-2 selectivity.
The compounds of the formula I of this invention can be administered via oral, parenteral, anal, buccal or topical routes to mammals (including humans, dogs, cats, horses and livestock).
In general, these compounds are most desirably administered to humans in doses ranging from 0.01 mg to 100 mg per kg of body weight per day, although variations will necessarily occur depending upon the weight, sex and condition of the subject being treated, the disease state being treated and the particular route of administration chosen. However, a dosage level that is in the range of from 0.1 mg to 10 mg per kg of body weight per day, single or divided dosage is most desirably employed in humans for the treatment of abovementioned diseases.
These compounds are most desirably administered to said non-human mammals, e.g. dogs, cats, horses or livestock in an amount, expressed as mg per kg of body weight of said member per day, ranging from about 0.01 mg/kg to about 20.0 mg/kg/day, preferably from about 0.1 mg/kg to about 12.0 mg/kg/day, more preferably from about 0.5 mg/kg to about 10.0 mg/kg/day and most preferably from about 0.5 mg/kg to about 8.0 mg/kg/day.
The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, ire., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, trochees, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from 5% to 70% by weight, preferably 10% to 50% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatine capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
A preferred composition for dogs comprises an ingestible liquid peroral dosage form selected from the group consisting of a solution, suspension, emulsion, inverse emulsion, elixir, extract, tincture and concentrate, optionally to be added to the drinking water of the dog being treated. Any of these liquid dosage forms, when formulated in accordance with methods well known in the art, can either be administered directly to the dog being treated, or may be added to the drinking water of the dog being treated. The concentrate liquid form, on the other hand, is formulated to be added first to a given amount of water, from which an aliquot amount may be withdrawn for administration directly to the dog or addition to the drinking water of the dog.
A preferred composition provides delayed-, sustained- and/or controlled-release of said anti-inflammatory selective COX-2 inhibitor. Such preferred compositions include all such dosage forms which produce xe2x89xa780% inhibition of COX-2 isozyme activity and result in a plasma concentration of said inhibitor of at least 3 fold the COX-2 IC50 for at least 4 hours; preferably for at least 8 hours; more preferably for at least 12 hours; more preferably still for at least 16 hours; even more preferably still for at least 20 hours; and most preferably for at least 24 hours. Preferably, there is included within the above-described dosage forms those which produce xe2x89xa780% inhibition of COX-2 isozyme activity and result in a plasma concentration of said inhibitor of at least 5 fold the COX-2 IC50 for at least 4 hours, preferably for at least 8 hours, more preferably for at least 12 hours, still more preferably for at least 20 hours and most preferably for at least 24 hours. More preferably, there is included the above-described dosage forms which produce xe2x89xa790% inhibition of COX-2 isozyme activity and result in a plasma concentration of said inhibitor of at least 5 fold the COX-2 IC50 for at least 4 hours, preferably for at least 8 hours, more preferably for at least 12 hours, still more preferably for at least 20 hours and most preferably for at least 24 hours.
For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The compounds of formula I may also be administered in the form of suppositories for rectal or vaginal administration of the active ingredient. These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature (for example, 10xc2x0 C. to 32xc2x0 C.) but liquid at the rectal temperature and will melt in the rectum or vagina to release the active ingredient. Such materials are polyethylene glycols, cocoa butter, suppository and wax.
For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.
For transdermal administration, transdermal patches prepared in accordance with well known drug delivery technology may be prepared and applied to the skin of a mammal, preferably a human or a dog, to be treated, whereafter the active agent by reason of its formulated solubility characteristics migrates across the epidermis and into the dermal layers of the skin where it is taken up as part of the general circulation, ultimately providing systemic distribution of the active ingredient over a desired, extended period of time. Also included are implants which are placed beneath the epidermal layer of the skin, i.e. between the epidermis and the dermis of the skin of the patient being treated. Such an implant will be formulated in accordance with well known principles and materials commonly used in this delivery technology and may be prepared in such a way as to provide controlled-, sustained- and/or delayed-release of the active ingredient into the systemic circulation of the patient. Such subepidermal (subcuticular) implants provide the same facility of installation and delivery efficiency as transdermal patches, but without the limitation of being subject to degradation, damage or accidental removal as a consequence of being exposed on the top layer of the patient""s skin.